Diabetes mellitus is often associated with significant cardiovascular injury. Recent data provide support for the hypothesis that activation of mineralocorticoid receptor (MR) contributes to diabetic vascular injury, though the mechanisms are uncertain. Consistent with this hypothesis, our pre-clinical studies in diabetic db/db mice demonstrate that blockade of MR reduces albuminuria and decreases glomerular and tubulointerstitial injury. Our studies in hypertensive, angiotensin II (ANGII)-infused animals demonstrate that MR antagonists reduce vascular inflammation and cardiac and renal injury. Furthermore, our clinical studies show that short-term treatment with the MR antagonist eplerenone improves myocardial perfusion reserve as compared to treatment with hydrochlorothiazide (HCTZ) in subjects with diabetes receiving angiotensin-converting enzyme (ACE) inhibition therapy. This observation is important as it suggests that MR antagonists are not working via a classical renal effect, but via an additional, volume control-independent mechanism. This proposal will test the hypothesis that activation of the MR contributes to progression of vascular disease in subjects with type 2 diabetes mellitus receiving ACE inhibitor therapy, and consequently, MR antagonists exert beneficial effects by reducing vascular dysfunction and injury, inhibiting ANGII vascular effects, and improving coronary circulatory and cardiac function. To address this hypothesis we will perform a prospective randomized, double-blind study in subjects with type 2 diabetes mellitus and hypertension receiving chronic ACE inhibitor therapy. Subjects will be randomized to one of three treatments: 1) MR antagonist spironolactone;2) HCTZ plus potassium;and 3) placebo. We will determine the effects of MR blockade in two specific aims. Aim 1 will assess cardiac function by measuring myocardial perfusion reserve and diastolic function and Aim 2 will assess renovascular function. These studies will provide new information about the mechanisms by which MR antagonists reduce diabetic cardiovascular injury, with the goal of introducing new, effective treatments of cardiovascular injury in individuals with diabetes through the addition of MR blockade to ACE inhibitor therapy. PUBLIC HEALTH RELEVANCE: Diabetes is an important cause of injury to blood vessels. Vascular injury leads to many health problems including heart damage, kidney failure, stroke, blindness and poor circulation in the legs. It is not completely known how diabetes causes this damage or how to prevent the damage. Recent studies in animals and humans suggest that a blood hormone (chemical) known as aldosterone causes damage to blood vessels. The goal of this research is to determine whether blocking the actions of aldosterone improves the function of vessels in the hearts and kidneys of patients with type 2 diabetes and whether this leads to improvements in heart function. If successful, this research will provide doctors with information about a new way to treat individuals with diabetes who have injuries to their blood vessels, heart and kidneys.